Heart disease and other forms of cardiovascular disease are leading causes of death in the industrialized world. While a great amount of money is spent each year on cardiovascular drugs, there are still great gains to be made by developing new drugs that treat cardiovascular diseases. Drug discovery and development requires that potential drugs must be examined for adverse cardiovascular effects, a process that is expensive and difficult. It is estimated that more than 40% of compounds that enter phase III clinical trials are dropped, often for toxicity. Off-target cardiac toxicity, or cardiotoxicity, is a significant problem in bringing a new drug to market.
Existing approaches to studying cardiotoxicity are lacking. Some approaches focus on studying a compound's tendency to block the ion channel encoded by the human ether-a-go-go related gene (hERG) as a proxy for cardiotoxicity, but this oversimplification likely keeps many promising drugs from being discovered. Other approaches test for prolongation of the QTc interval in non-human animals, but animal studies are expensive and slow. Other approaches use the technique of patch-clamp electrophysiology on primary or human stem cell-derived myocytes to probe effects of compounds on the action potential waveform, but patch clamp measurements require a skilled operator and are very laborious. Patch clamp measurements also fail to probe the calcium handling dynamics of the myocyte. A think tank sponsored by the Food and Drug Administration has proposed a Comprehensive in vitro Proarrhythmia Assay (CiPA) to potentially evaluate drug effects on multiple ion channels. The CiPA initiative seeks to probe cardiotoxicity in human stem cell-derived cardiomyocytes, but an accurate, and rapid assay is needed to quantify voltage and calcium handling, under defined pacing conditions.